Chapters authored
Zinc-Binding B-Box Domains with RING Folds Serve Critical Roles in the Protein Ubiquitination Pathways in Plants and Animals
Protein ubiquitination is an essential cellular process that maintains protein homeostasis, regulates protein, and cell functions, and removes aggregated and misfolded protein. Disruption in function of any of the protein components of the ubiquitination pathway is associated with human diseases including cancers. An important member in the ubiquitination cascade is the very large E3 ligase family that directs substrate modification. The RING-type E3 ligases possess a cysteine/histidine-rich zinc-binding RING domain that confers ligase functionality. RING domains adopt a canonical ββα-fold. TRIM proteins represent a novel class of RING-type E3 ligase. TRIM proteins consist of an N-terminal RING domain followed by one or two B-box domains. The two types of B-box domains play essential roles in protein ubiquitination by contributing to substrate targeting, ligase activity enhancement, and redundancy of ligase activity. This review presents a general background of the B-box domains, a structural and functional comparison with RING domains, and a summary of recent work demonstrating their role in proteolysis. We discuss new findings that reveal B-box domains which are ubiquitous and are found in non-TRIM plant proteins without the adjacent RING domain, indicating that B-boxes are members of RING-class E3 ligases.
Part of the book: Ubiquitin Proteasome System
Review of the Structural Basis of Human E2 Conjugating Enzymes in Complexed with RING E3 Ligases
Protein ubiquitination is a post-translational modification that controls essential biological processes through its regulation of protein concentration, function, and cellular location. RING E3 ligases are a critical component of a three-enzyme cascade that facilitates the ubiquitination of proteins. RING-type E3 ligases represent one class of E3 ligases that function by binding the substrate protein and ubiquitin-conjugating enzymes (E2s). Proteins exhibiting RING-type E3 ligase activities do so via a domain that adopts a ββα-RING fold and coordinates two zinc ions. To date, structural studies show that the RING domain interacts with the catalytic domain of the E2 enzyme. The catalytic domain is approximately 150 amino acids and adopts a canonical structure consisting of four α-helices and 3–4 β-strands. Structural analyses of RING–E2 complexes reveal that RING domains interact on a similar surface of the E2 enzyme. We postulate that the mechanism of interaction between an E2 enzyme and its cognate RING E3 domain may contribute to the extent of substrate modification. In this review, we compare the primary and secondary structures of human E2 enzymes and examine their quaternary structure with RING domains. Our analyses reveal the interactions appear to be relatively conserved with similar types of amino acids involved.
Part of the book: Hydrolases